BronchodilatorsBronchodilators((支气管扩张药支气管扩张药 ))

Huifang Tang (汤慧芳 )Department of PharmacologyZhejiang university, school of

Medicinetanghuifang@zju.edu.cn

Drugs acting on respiratory systemCough Cough antitussive drugsantitussive drugs centrally actingcentrally acting peripherally actingperipherally actingSputumSputum expectorant drugs expectorant drugs sputum-diluting drugssputum-diluting drugs mucolytic drugsmucolytic drugsAsthmaAsthma antiasthmatic drugs antiasthmatic drugs BBronchodilatorsronchodilators receptor agonistsreceptor agonists theophyllinestheophyllines muscarinic antagonistsmuscarinic antagonists AAnti-inflammatory drugsnti-inflammatory drugs glucocorticosteroidsglucocorticosteroids mediator release mediator release

inhibitorsinhibitors

Antiasthmatic drugs

Airway Airway inflammationinflammation

bronchoconstrictibronchoconstrictionon

Airway hyperresponsiveness

Immunological and non-Immunological and non-immunological stimuliimmunological stimuli

Wheezing (asthmatic symptoms)

glucocorticosteroids

Disodium cromoglycate

Leukotriene modifiers

2 receptor agonists

Theophylline

Muscerinic antagonists

BronchodilatorsBronchodilators

Receptor agonistsReceptor agonists

Non-selectiveNon-selective ：： adrenaline, adrenaline,

isoprenalineisoprenaline

22-selective: -selective:

moderate-acting:moderate-acting: salbutamol, salbutamol,

terbutalineterbutaline

long-acting:long-acting: salmeterol, formoterolsalmeterol, formoterol

Theophyllines:Theophyllines: aminophyllineaminophylline

Muscarinic antagonists:Muscarinic antagonists: ipratropium ipratropium

bromidebromide

1. 1. receptor agonists receptor agonists

去甲肾上腺素去甲肾上腺素

异丙肾上腺素异丙肾上腺素

沙丁胺醇沙丁胺醇

福莫特罗福莫特罗

肾上腺素肾上腺素

non-selectivity non-selectivity

22 receptor selective agonists receptor selective agonists

Salbuterol Salbuterol 沙丁胺醇沙丁胺醇

1. 1. Pharmacological effectsPharmacological effects Relaxing bronchial smooth musclesRelaxing bronchial smooth muscles

2. 2. Clinical usesClinical uses Controlling asthmatic symptomsControlling asthmatic symptoms

Given by Given by inhalationinhalation, oral or injection, oral or injection

3. 3. Adverse effectsAdverse effects Skeletal muscle tremorSkeletal muscle tremor

Cardiac stimulation (larger doses)Cardiac stimulation (larger doses)

Dysfunction of metabolism Dysfunction of metabolism (hypokalemia, (hypokalemia, etcetc.).)

Bronchial dilators

Selectivity of Selectivity of 22 agonistsagonists

22 receptor selective agonists receptor selective agonists ：：

LLong-actingong-acting

Salmeterol Salmeterol 沙美特沙美特罗罗

Formoterol Formoterol 福莫特福莫特罗罗

Bronchial dilators

1. 1. receptor agonists receptor agonists

维兰特罗奥达特罗茚达特罗

TheophyllinesTheophyllines

Aminophylline 氨茶碱

N

N N

NH3C H

CH2NH2

2H2OCH2NH2

O

O

CH3--

--

--

--

2

. .

Theophyllines:Theophyllines:

One type of xanthine derivatives (One type of xanthine derivatives ( 甲基黄嘌呤类衍生甲基黄嘌呤类衍生物物 ))

Bronchial dilatorsBronchial dilators

1. Pharmacological effects1. Pharmacological effects

Inhibiting phosphodiesterase(PDE); Inhibiting phosphodiesterase(PDE);

Blocking adenosine receptors;Blocking adenosine receptors;

Increasing catecholamine release;Increasing catecholamine release;

Immunomodulation;Immunomodulation;

Increasing contractilityIncreasing contractility of of respiratory respiratory

muscle(diaphragm muscle);muscle(diaphragm muscle);

Diuretic, Diuretic,

CNS stimulation,CNS stimulation,

Gastric acid secretion, etc.Gastric acid secretion, etc.

Bronchial dilators

2. 2. Clinical usesClinical uses Bronchial asthma (Bronchial asthma (p.o.p.o., , i.v.i.v.))

Others: Others: acute pulmonary edema, acute pulmonary edema, etc.etc.

Slow-release theophylline (for control of

nocturnal asthma) is the most commonly

used methylxanthine.

Aminophylline

pentoxifylline, is promoted as a

remedy for intermittent claudication;

Bronchial dilators

Common adverse effects:Gastrointestinal distress, tremor, and insomnia.

Severe nausea and vomiting, hypotension, cardiac

arrhythmias, Seizures

Very large overdoses (eg, in suicide attempts) are

potentially lethal because of arrhythmias and

seizures.

Beta blockers are useful in reversing severe

cardiovascular toxicity from theophylline.

Muscarinic antagonists—— M receptor blocking

Bronchial dilators

Muscarinic antagonists

—— M receptor blockingIpratropine 异丙托溴铵，异丙托

品O

C

CH2

CH2 CH2

C6H5CHOCH

CH3

CH3

CH

NCH3

CH

OH

(CH3)2CH

Bronchial dilators

Mechanism of Action and EffectsMechanism of Action and Effects

When given by aerosol, ipratropium and When given by aerosol, ipratropium and tiotropium competitively block muscarinic tiotropium competitively block muscarinic receptors in the airways and effectively receptors in the airways and effectively prevent bronchoconstriction mediated by prevent bronchoconstriction mediated by vagal dischargevagal discharge.

Muscarinic antagonists reverse Muscarinic antagonists reverse bronchoconstriction in some asthma bronchoconstriction in some asthma patients patients (especially children) (especially children) and in many and in many patients with COPD. patients with COPD.

They have no effect on the chronic They have no effect on the chronic inflammatory aspects of asthma.inflammatory aspects of asthma.

Clinical Use and ToxicityClinical Use and Toxicity

Ipratropium and tiotropium are useful in Ipratropium and tiotropium are useful in one third to two thirds of asthmatic one third to two thirds of asthmatic patients; β2 agonists are effective in patients; β2 agonists are effective in almost all. almost all.

For acute bronchospasm, therefore, the For acute bronchospasm, therefore, the β agonists are usually preferred.β agonists are usually preferred.

However, in COPD, which is often However, in COPD, which is often associated with acute episodes of associated with acute episodes of bronchospasm, the antimuscarinic bronchospasm, the antimuscarinic agents may be more effective and less agents may be more effective and less toxic than β agonists.toxic than β agonists.

Novel class of BrochodilatorsNovel class of Brochodilators

Aerosol Aerosol inhalatioinhalatio

nn

Spacer used for aerosol Spacer used for aerosol inhalationinhalation

定量手控定量手控

气雾器气雾器

Spacer will aid Spacer will aid patients to inhale patients to inhale the aerosolized the aerosolized drugs easierdrugs easier

Outcome of different sized Outcome of different sized particles:particles:

> 10μm: mouth and > 10μm: mouth and oropharynxoropharynx

< 0.5μm: inhaled to the < 0.5μm: inhaled to the alveoli and subsequently alveoli and subsequently exhaled without being exhaled without being deposited in the lungdeposited in the lung

1-5μm: the most effective1-5μm: the most effective

Reference

Pharmacology and therapeutics of bronchodilators.Cazzola M, Page CP, Calzetta L, Matera MG. Pharmacol Rev. 2012 Jul;64(3):450-504. doi: 10.1124/pr.111.004580. Review.